US20050056814A1 - Electroactive probe comprising a chelating agent and a metal ion - Google Patents

Electroactive probe comprising a chelating agent and a metal ion Download PDF

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Publication number
US20050056814A1
US20050056814A1 US10/496,655 US49665504A US2005056814A1 US 20050056814 A1 US20050056814 A1 US 20050056814A1 US 49665504 A US49665504 A US 49665504A US 2005056814 A1 US2005056814 A1 US 2005056814A1
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Prior art keywords
antiligand
probe
electroactive
chelating agent
polymer
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US10/496,655
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English (en)
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Francis Garnier
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Biomerieux SA
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Biomerieux SA
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Assigned to BIO MERIEUX reassignment BIO MERIEUX ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GARNIER, FRANCIS
Publication of US20050056814A1 publication Critical patent/US20050056814A1/en
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    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01B—CABLES; CONDUCTORS; INSULATORS; SELECTION OF MATERIALS FOR THEIR CONDUCTIVE, INSULATING OR DIELECTRIC PROPERTIES
    • H01B1/00—Conductors or conductive bodies characterised by the conductive materials; Selection of materials as conductors
    • H01B1/06—Conductors or conductive bodies characterised by the conductive materials; Selection of materials as conductors mainly consisting of other non-metallic substances
    • H01B1/12—Conductors or conductive bodies characterised by the conductive materials; Selection of materials as conductors mainly consisting of other non-metallic substances organic substances
    • H01B1/124—Intrinsically conductive polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G61/12—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule
    • C08G61/122—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides
    • C08G61/123—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides derived from five-membered heterocyclic compounds
    • C08G61/124—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides derived from five-membered heterocyclic compounds with a five-membered ring containing one nitrogen atom in the ring
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
    • G01N27/3277—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction being a redox reaction, e.g. detection by cyclic voltammetry
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01B—CABLES; CONDUCTORS; INSULATORS; SELECTION OF MATERIALS FOR THEIR CONDUCTIVE, INSULATING OR DIELECTRIC PROPERTIES
    • H01B1/00—Conductors or conductive bodies characterised by the conductive materials; Selection of materials as conductors
    • H01B1/06—Conductors or conductive bodies characterised by the conductive materials; Selection of materials as conductors mainly consisting of other non-metallic substances
    • H01B1/12—Conductors or conductive bodies characterised by the conductive materials; Selection of materials as conductors mainly consisting of other non-metallic substances organic substances
    • H01B1/122—Ionic conductors

Definitions

  • the invention relates to organic electrodes prepared from electroactive polymers to which are bonded antiligands intended to interact specifically with ligands.
  • the specific interaction of the antiligand with the ligand results in a perceptible and selective variation in the electrochemical properties of the electroactive polymer, such as a decrease in the electroactivity of said polymer.
  • This variation which depends on the concentration of grafted ligand, is observed, optionally measured and directly correlated with the amount of grafted ligand.
  • One of the essential applications of this technique is thus the detection, identification and optionally assay of a ligand present in a biological sample.
  • the abovementioned variation is of potentiometric type, such as a variation in the oxidation potential of the electroactive polymer before and after interaction, or of amperometric type, such as a variation in the current for oxidation or reduction of the polymer before and after hybridization, determined at a predetermined potential.
  • WO-A-95/29199 discloses a polypyrrole composed of monomers each consisting of a pyrrole ring covalently substituted on the carbon in the 3-position of the pyrrole ring by a polynucleotide probe.
  • the polypyrrole thus obtained is applied to the detection, and optionally assay, of ligands, in vitro or in vivo.
  • the latter In order to precisely characterize the electrochemical response of the polymer, the latter must exhibit a high electroactivity.
  • chelating agents such as NTA (nitrilotriacetate) or IDA (iminodiacetate)
  • NTA nitrilotriacetate
  • IDA iminodiacetate
  • IMAC immobilized metal affinity chromatography
  • the IDA was charged with metal ions, such as Zn 2+ , Cu 2+ or Ni 2+ , and was used to purify proteins or peptides.
  • Metals have specific oxidation potentials which are characteristic and which make possible their detection and their assay by electrochemistry.
  • the detection limit of a complexing device is dependent on the amount of complexing agent used.
  • One of the possible solutions for lowering the detection limit consists of the confinement of ionic entities on the measuring electrode through the agency of the attachment of chelating agents to the electrode.
  • the Applicant Company has found, surprisingly, that the use of a conducting polymer as support for these chelating agents makes it possible to retain, even for relatively thick deposits of the order of approximately one hundred micrometers, the continuity of the conduction and thus to lower the detection limit to thresholds of the order of 10 ⁇ 9 to 10 ⁇ 10 molecules per cm 2 .
  • a first subject matter of the invention is an electroactive complex composed of an electroactive polymer which is a homopolymer or copolymer of at least two monomers and which is functionalized by a chelating agent complexed with a metal ion, an antiligand and a ligand which has specifically interacted with said antiligand.
  • antiligand and “ligand” refer without distinction to biological molecules, such as polynucleotides or peptides, but also to chemical molecules.
  • the antiligand is capable of interacting specifically with the ligand to form a ligand/antiligand conjugate. Mention may be made, as examples of conjugates, of any peptide/antibody, antibody/hapten, hormone/receptor, polynucleotide/polynucleotide or polynucleotide/nucleic acid reversible pair and the like.
  • polynucleotide denotes a sequence of at least five natural or modified nucleotides (deoxyribonucleotides or ribonucleotides) which is capable of hybridizing, under appropriate hybridization conditions, with an at least partially complementary polynucleotide.
  • modified polynucleotides is understood to mean, for example, a nucleotide comprising a modified base and/or comprising a modification at the level of the internucleotide bond and/or the level of the backbone.
  • ⁇ -Oligonucleotides such as those disclosed in FR-A-2 607 507, and the PNAs which form the subject of the paper by M. Egholm et al., J. Am. Chem. Soc., 114, 1895-1897 (1992), are examples of polynucleotides composed of nucleotides possessing a modified backbone.
  • peptide means in particular any sequence of at least two amino acids, such as protein, protein fragment or oligopeptide, which have been extracted, separated, isolated or synthesized, such as a peptide obtained by chemical synthesis or by expression in a recombinant organism.
  • antibody defines any monoclonal or polyclonal antibody, any fragment of said antibody, such as the Fab, Fab′2 or Fc fragments, and any antibody obtained by genetic modification or recombination.
  • to graft to bond
  • to bind to attach
  • to attach in the absence of any indication, are employed without distinction in the present text to denote a connection between two entities, without defining the chemical nature thereof. It can thus be a weak bond or a covalent bond.
  • a connecting group according to the invention connects, via a covalent bond, two chemical entities, after interaction of said two entities, at least one having been activated or activatable beforehand, for the purpose of this interaction, by an activated or activatable group.
  • the bonding group can thus result from the reaction of said activated or activatable group of one entity with a reactive functional group of the other entity, and vice versa, or from the reaction of said activated or activatable group of one entity with another said activated or activatable group of the other entity.
  • activated group is understood to mean a group which makes possible, through its agency, the interaction of the entity to which it is attached with another entity.
  • it can be an activated ester group, such as the —CO—[O—N-phthalimide] group.
  • activatable group is understood to mean a group which can be converted to an activated group, for example under certain reaction conditions or when brought into contact with an activated group capable of interacting with it.
  • the electroactive polymer of the invention is any polymer which is electroactive in water.
  • the metal ions as present in the complex of the invention are ions capable of retaining a few sites available for complexing with the antiligand after they have complexed with a chelating agent. These available sites are neutralized by water if there is no subsequent complexing, for example with said antiligand.
  • the chelating agents used in the invention are chelating agents which complex with the metal ion so that the complexing leaves coordination sites of the ion available for subsequent complexing, in the present case with an antiligand.
  • NTA is a tetradentate chelating agent which is suitable for the purposes of the invention. Its complexing with a metal ion, such as copper or nickel, results in the occupation of four of the six coordination sites of said ion, which leaves two sites available for interacting with an antiligand. NTA binds metal ions in a more stable way than other resins available for chelation.
  • IDA Another example of a chelating agent suitable for the purposes of the invention is IDA, which has three sites available for chelation.
  • the chelating agent is also bonded to the conducting polymer. This bonding is bonding through the agency of a bonding group as defined above and takes place in a covalent manner.
  • the ligand and the antiligand are biological or chemical molecules as indicated above. They can be labeled by a tracer capable of directly or indirectly generating a signal, according to techniques widely known to a person skilled in the art, insofar as detection additional to the electrochemical detection is desired.
  • the antiligand can be bonded to the metal ion via a bonding intermediate, the property of which is to improve the bonding of the antiligand to the metal ion.
  • a bonding intermediate the property of which is to improve the bonding of the antiligand to the metal ion.
  • An example of such an intermediate is histidine or one of its polymeric derivatives, such as polyhistidine.
  • the electroactive polymer is chosen from polypyrrole, polyacetylene, polyazine, poly(p-phenylene), poly(p-phenylene vinylene), polypyrene, polythiophene, polyethylenedioxythiophene, polyfuran, polyselenophene, polypyridazine, polycarbazole, polyaniline or double-stranded polynucleotides, and/or
  • the electroactive polymer is a polypyrrole composed of at least two monomers each consisting of a pyrrole ring.
  • the polypyrrole is a copolymer and comprises a monomer, the pyrrole ring of which is substituted by a —CH 2 —COOH or —CH 2 —CH 2 OH group.
  • an electroactive probe composed of an electroactive polymer which is a homopolymer or copolymer of at least two monomers and which is functionalized by a chelating agent complexed with a metal ion and an antiligand capable of interacting specifically with a ligand.
  • the electroactive probe of the invention has the characteristics of polymer, metal ion, chelating agent and antiligand as indicated above for the complex of the invention.
  • the electropolymerization stage is carried out by using techniques well known to a person skilled in the art. For example, it can be carried out by subjecting the monomers to variations in electric potential which are sufficient to bring about polymerization by successive oxidation and successive reduction; or else by polymerization with a controlled current (chronopotentiometry) or with a controlled potential (chronoamperometry).
  • the probes of the invention can be prepared by a process comprising the following stages:
  • the polymer is a polypyrrole composed of at least two pyrrole monomers, at least one of which is substituted in the 3-position with an activated ester group.
  • the invention also relates to a method for the detection of a ligand in a biological sample, according to which said probe is brought into contact under reaction conditions appropriate for the specific ligand/antiligand interaction and a difference in potential or a variation in current between the probe before bringing into contact and the probe after bringing into contact is demonstrated or quantified.
  • reaction conditions depend on the type of reaction concerned.
  • the specific ligand/antiligand interaction is a hybridization.
  • the reaction conditions appropriate for a hybridization are widely known to a person skilled in the art.
  • the specific ligand/antiligand interaction is that, for example, of an antigen/antibody reaction.
  • the appropriate conditions for such detection are also widely known to a person skilled in the art.
  • the antiligand is bonded to histidine or one of its polymeric derivatives.
  • an electrode all or part of the surface of which is coated with a probe defined above.
  • Such an electrode can be obtained by any conventional technique well known to a person skilled in the art.
  • this preparation can be carried out by depositing a polymer of the invention at the surface of an electrode made of platinum, of gold, of chromium or of titanium covered with gold, of glassy carbon or of a conducting oxide, such as tin oxide or a mixed oxide of tin and of indium.
  • the 3-carboxymethylpyrrole-NHP monomer was synthesized by esterifying the carboxyl group of 3-pyrroleacetic acid with N-hydroxyphthalimide and dicyclocarboxydiimide, as catalyst, in chloroform, as solvent, at ambient temperature.
  • the reaction scheme is presented below.
  • a 0.1M solution of 3-carboxymethylpyrrole-NHP monomer is prepared in freshly distilled anhydrous acetonitrile in the presence of an electrolyte (LiClO 4 , 0.5M).
  • This monomer is polymerized in a 4-compartment cell using a 0.7 cm 2 platinum electrode, an auxiliary platinum electrode and a saturated calomel electrode as reference electrode, at the controlled potential of 0.9 V, to produce the poly(3-carboxymethylpyrrole-NHP) film.
  • the film obtained is washed with acetone and dried.
  • the electroactivity is subsequently measured in an acetonitrile medium comprising 0.1M LiClO 4 as electrolyte after purging with argon to remove oxygen.
  • Cyclic voltametry is recorded at the rate of 20 mV/s, as represented in FIG. 1 .
  • the electrode is washed with acetone and dried.
  • the electrode is immersed in a saturated aqueous solution of NTA or IDA at ambient temperature for 12 hours, washed with ultrapure water and dried.
  • the synthesis of poly(3-carboxymethylpyrrole-IDA) or of poly(3-carboxymethylpyrrole-NTA) is represented below:
  • the electrode obtained is washed with ultrapure water and dried, and the electroactivity is monitored in an aqueous medium comprising 0.5M NaCl.
  • the electrochemical analysis is represented in FIG. 2 .
  • the electrochemical signal is stable and reversible in an aqueous medium.
  • Poly(3-carboxymethylpyrrole-NHP) films with different thicknesses were prepared and the films obtained were grafted with NTA.
  • the electrochemical response recorded in an aqueous medium in the presence of 0.5M NaCl, confirms the presence of an electrochemically active film in an aqueous medium.
  • Comparison of the charge of poly(3-carboxymethylpyrrole-NHP) deposited at the beginning on the electrode and the calculated charge of NTA grafted to the film suggests that the efficiency for grafting of NTA or of IDA to the film 100%.
  • the amount of NTA or of IDA grafted to the poly(3-carboxy)pyrrole film depends on the amount of 3-carboxymethylpyrrole-NHP units present on the electrodes, as illustrated by the curves of FIG. 3 .
  • the electrode comprising the poly(3-carboxymethylpyrrole-NTA) film was analyzed electrochemically in an aqueous medium, washed with deionized water and dried, and it is subsequently immersed in an aqueous solution of CuCl 2 in the presence of 0.5M NaCl at ambient temperature for 3 hours.
  • the electrode is subsequently rinsed in deionized water, dried and electrochemically analyzed in an aqueous solution comprising 0.5M NaCl.
  • the electrodes comprising a polypyrrole-NTA/Cu 2+ film are washed with water, then dried and immersed in a PBS buffer solution of polyhistidine with a molecular weight of 6300 g in an amount which is equimolecular with the amount of copper complexed to the polypyrrole-NTA film comprising NaCl for one hour at ambient temperature.
  • the electrodes comprising grafted polyhistidine obtained above are treated by immersion in an aqueous EDTA solution at ambient temperature for 15 minutes, rinsed and then dried.
  • the immobilized protein RH24 is a protein modified by addition of 6 histidine amino acids in the N-terminal position of the P24 protein naturally synthesized by Escherichia coli with a theoretical molecular mass of 26 950 g.
  • the grafting is carried out by incubating 5 nmol of antigen for 3 hours at ambient temperature on the Cu 2+ /polypyrrole-NTA film. They are subsequently analyzed electrochemically in an aqueous solution comprising 0.5M NaCl.
  • Cyclic voltammetry is recorded at the rate of 20 mV/s.
  • Detection is carried out by immersion of the electrode comprising a polypyrrole-NTA film complexed by Cu 2+ ions on which is immobilized an antigen in a solution of 0.6 nmol of antibody specific to the antigen.
  • Cyclic voltammetry is recorded at the rate of 20 mV/s.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Electrochemistry (AREA)
  • General Physics & Mathematics (AREA)
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  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
  • Polyoxymethylene Polymers And Polymers With Carbon-To-Carbon Bonds (AREA)
US10/496,655 2001-11-30 2002-12-02 Electroactive probe comprising a chelating agent and a metal ion Abandoned US20050056814A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0115668 2001-11-30
FR0115668A FR2833013B1 (fr) 2001-11-30 2001-11-30 Sonde electroactive comportant un agent chelatant et un cation metallique
PCT/FR2002/004137 WO2003046052A1 (fr) 2001-11-30 2002-12-02 Sonde electroactive comportant un agent chelatant et un ion metallique

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US (1) US20050056814A1 (de)
EP (1) EP1458790A1 (de)
JP (1) JP2005510606A (de)
AU (1) AU2002365306A1 (de)
FR (1) FR2833013B1 (de)
WO (1) WO2003046052A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114152655A (zh) * 2021-12-31 2022-03-08 常州大学 用于谷氨酸对映体手性识别的聚苯乙烯与L-Phe复合物修饰电极及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5210217A (en) * 1987-10-29 1993-05-11 Miles Inc. Substituted bithiophenes and dithienylpyrroles
US5644064A (en) * 1993-07-16 1997-07-01 Eletricite De France - Service National Derivatives of polyethers and of pentacyclic heterocycles, their polymers and their applications, particularly to the complexing of metal ions
US6096825A (en) * 1994-04-22 2000-08-01 Bio Merieux Electrically conductive electroactive functionalized conjugated polymers, and uses thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2351479A1 (en) * 1998-11-19 2000-06-02 Bio Merieux Electrically conductive electroactive functionalized conjugated polymers, and uses thereof
FR2808024B1 (fr) * 2000-04-21 2006-09-15 Bio Merieux Complexe electroactif, sonde electroactive et procede de preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5210217A (en) * 1987-10-29 1993-05-11 Miles Inc. Substituted bithiophenes and dithienylpyrroles
US5644064A (en) * 1993-07-16 1997-07-01 Eletricite De France - Service National Derivatives of polyethers and of pentacyclic heterocycles, their polymers and their applications, particularly to the complexing of metal ions
US6096825A (en) * 1994-04-22 2000-08-01 Bio Merieux Electrically conductive electroactive functionalized conjugated polymers, and uses thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114152655A (zh) * 2021-12-31 2022-03-08 常州大学 用于谷氨酸对映体手性识别的聚苯乙烯与L-Phe复合物修饰电极及其制备方法

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Publication number Publication date
WO2003046052A1 (fr) 2003-06-05
FR2833013B1 (fr) 2005-06-24
EP1458790A1 (de) 2004-09-22
JP2005510606A (ja) 2005-04-21
AU2002365306A1 (en) 2003-06-10
FR2833013A1 (fr) 2003-06-06

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